Multicellular organisms have intrinsic defenses to protect against the development of mutations and cancer. One such defense mechanism is the signaling pathways regulated by tumor protein p53 (encoded by the gene TP53), which is a critical suppressor of cancer. Referred to as the “guardian of the genome,” p53 is able to halt cell division when DNA damage is detected and either initiate correction of the mutation, or trigger apoptosis if the damage is irreparable (Blagosklonny. Int J Cancer, 98: 161-166(2002)). Humans contain one copy (two alleles) of TP53, and both functioning alleles are crucial to prevent cancer development. The absence of even one functional allele leads to Li-Fraumeni Syndrome (LFS), a cancer predisposition in which patients have a 90% chance of developing cancer during their lifetime (McBride et al. Nat Rev Clin Oncol; 11(5): 260-271 (2014)). Inactivation of p53 also can lead to cancer (Lane, D P. Nature; 358(6381): 15-16 (2014); Hanahan et al. Cell; 144(5): 646-674 (2011)), and in humans p53 function naturally decreases with age (Feng et al., PNAS; 104(42): 16633-16638 (2007)), leaving half of all men and a third of all women susceptible to developing cancer during their lifetime (American Cancer Society; Cancer Facts & FIGURES (2015)). Mutations of p53 have been identified in numerous human cancers (Hollstein et al., Science; 253(5015): 49-53 (1991)).
Researchers have naturally focused on combating cancer by utilizing the protective properties of p53. For example, retrovirus- and adenovirus-mediated TP53-gene therapies have been developed to deliver human p53 to cancer cells (Cai et al. Hum Gene Ther: 4: 617-624 (1993); Brandt et al. Am J Epidemiol; 90: 484-500 (1969)), and the accumulation of p53 can be induced by disrupting its negative regulation by mouse double minute 2 (MDM2) (Vassilev et al. Science; 3i03: 844-848 (2004)). However these therapies have primarily focused on restoring the activity of wild type p53 in humans, or eliminating cancer cells with mutant p53.
Given that each cell division can potentially introduce a new genetic mutation, it was originally suspected that in larger organisms (which naturally require a greater number of cell divisions) there would be an increase in the number of mutated cells (Tomasetti et al., Science; 347(6217): 78-81 (2015)). If all mammalian cells are equally susceptible to oncogenic mutations, then cancer risk should increase with body size (number of cells) and species lifespan (number of cell divisions). However this theory was disproved over 35 years ago, as cancer incidence across animals does not appear to increase for larger body size and lifespan (Caulin et al., Trends Ecol Evolut; 26(4): 175-182 (2011); Peto et al., Br J Cancer; 32(4): 411-426 (1975)). The cellular and molecular mechanisms of this resistance to cancer in larger animals are not clearly understood, however a recent study has shown that elephants are especially resistant to developing cancer (Abegglen et al. JAMA; 314(17): 1850-60 (2015)). It was also discovered that elephants carry extra copies of the TP53 gene. Follow up studies showed that elephant p53 (EP53) is especially effective at killing cancer cells, even when the cancer cells already contained human p53.
There remains a need for compositions and methods to more effectively restore p53 function to cancerous cells. The invention provides such compositions and methods.